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AIM: To report a Phase I study of subcutaneous glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist BI 456906 versus placebo in healthy Japanese men with overweight/obesity. MATERIALS AND METHODS: We investigated multiple rising doses of BI 456906 escalated over 16 weeks (maximum doses: 1.8 mg once weekly [dose group {DG} 1], 4.8 mg once weekly [DG 2] and 2.4 mg twice weekly [DG 3]) in Japanese men with a body mass index of 23 to 40 kg/m2 . RESULTS: Thirty-six participants were treated (n = 9 per DG and placebo). Overall, 10 participants (37.0%) treated with BI 456906 withdrew from dose escalation due to adverse events (amylase increase, n = 1; decreased appetite, n = 9), and the proportion of participants was higher in DG 2 (n = 6, 66.7%) versus DGs 1 and 3 (both n = 2, 22.2%). No participants receiving placebo withdrew from dose escalation. BI 456906 exposure increased with dose and dose escalation in each DG. Treatment with BI 456906 decreased placebo-corrected bodyweight after 16 weeks (placebo +1.06%): DG 1, -5.57%; DG 2, -12.37%; DG 3, -9.62%. Paracetamol absorption decreased in Week 1 for DGs 2 and 3, indicating transient delayed gastric emptying. BI 456906 reduced plasma alanine and glucagon levels, indicating indirect target engagement at GCGRs and GLP-1Rs. Drug-related adverse events were reported for all participants receiving BI 456906 and four receiving placebo, the most frequent being decreased appetite (n = 24, 66.7%). CONCLUSIONS: BI 456906 showed no unexpected tolerability concerns and it reduced placebo-corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks of treatment.

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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Receptores de Glucagón , Humanos , Masculino , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Pueblos del Este de Asia , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Sobrepeso/complicaciones , Sobrepeso/tratamiento farmacológico , Receptores de Glucagón/agonistas

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INTRODUCTION: Prevalence of colorectal neoplasms varies by polygenic risk scores (PRS). We aimed to assess to what extent a PRS might be relevant for defining personalized cutoff values for fecal immunochemical tests (FITs) in colorectal cancer screening. METHODS: Among 5,306 participants of screening colonoscopy who provided a stool sample for a quantitative FIT (Ridascreen Hemoglobin or FOB Gold) before colonoscopy, a PRS was determined, based on the number of risk alleles in 140 single nucleotide polymorphisms. Subjects were classified into low, medium, and high genetic risk of colorectal neoplasms according to PRS tertiles. We calculated positive predictive values (PPVs) and numbers needed to scope (NNS) to detect 1 advanced neoplasm (AN) by the risk group, and cutoff variation needed to achieve comparable PPVs across risk groups in the samples tested with Ridascreen (N = 1,271) and FOB Gold (N = 4,035) independently, using cutoffs yielding 85%, 90%, or 95% specificity. RESULTS: Performance of both FITs was very similar within each PRS group. For a given cutoff, PPVs were consistently higher by 11%-15% units in the high-risk PRS group compared with the low-risk group (all P values < 0.05). Correspondingly, NNS to detect 1 advanced neoplasm varied from 2 (high PRS, high cutoff) to 5 (low PRS, low cutoff). Conversely, very different FIT cutoffs would be needed to ensure comparable PPVs across PRS groups. DISCUSSION: PPVs and NNS of FITs varied widely across people with high and low genetic risk score. Further research should evaluate the relevance of these differences for personalized colorectal cancer screening.

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Colonoscopía , Sangre Oculta , Heces , Humanos , Valor Predictivo de las Pruebas , Factores de Riesgo

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BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

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Metilenotetrahidrofolato Reductasa (NADPH2) , Posmenopausia , Anciano , Biomarcadores , Carbono/metabolismo , Femenino , Ácido Fólico , Genotipo , Antígenos de Histocompatibilidad , N-Metiltransferasa de Histona-Lisina/genética , Homocisteína , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Persona de Mediana Edad , Posmenopausia/genética , Salud de la Mujer

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Neoplasias Colorrectales , Detección Precoz del Cáncer , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Humanos , Tamizaje Masivo , Sangre Oculta

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OBJECTIVE: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. SUMMARY BACKGROUND DATA: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. METHODS: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. RESULTS: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [ORSEER-18 = 1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. CONCLUSIONS: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.

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Adenocarcinoma/patología , Adenocarcinoma/cirugía , Ganglios Linfáticos/patología , Metástasis Linfática , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Adenocarcinoma/mortalidad , Estudios de Cohortes , Humanos , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático , Análisis Multivariante , Estadificación de Neoplasias , Países Bajos/epidemiología , Neoplasias Pancreáticas/mortalidad , Tasa de Supervivencia , Estados Unidos/epidemiología

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BACKGROUND: Resection is the cornerstone of curative treatment for many nonmetastatic gastric cancers (GCs), but the population treatment patterns remains largely unknown. This large international population-based study aimed at investigating the treatment patterns and trends for nonmetastatic GC in Europe and the United States and at exploring factors associated with resection. METHODS: Data of patients with microscopically confirmed primary invasive GC without distant metastasis from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, Slovenia, and Estonia and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program were retrieved. Age-standardized treatment rates were computed and trends were evaluated using linear regression. Associations of resection with patient and tumor characteristics were analyzed using multivariable-adjusted log-binomial regression. Analysis was performed in each country respectively without pooling. RESULTS: Together 65 707 nonmetastatic GC patients diagnosed in 2003-2016 were analyzed. Age-standardized resection rates significantly decreased over years in all countries (by 4-24%). In 2013-2014, rates varied greatly from 54 to 75%. Patients with increasing ages, cardia cancers, or cancers invading adjacent structure were significantly less frequently resected. Resection was further associated with sex, performance status, comorbidities, tumor histology, tumor size, hospital type, and hospital volume. Association patterns and strengths varied across countries. After multivariable adjustment, resection rates remained decreasing (prevalence ratio = 0.97-0.995 per year), with decreasing trends consistently seen in various subgroups. CONCLUSIONS: Nonmetastatic GCs were less frequently resected in Europe and the United States in the early 21st century. Resection rates varied greatly across countries and appeared not to be optimal. Various factors associated with resection were revealed. Our findings can help to identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based GC management strategies. In Europe and the United States, nonmetastatic gastric cancers were less frequently resected in the early 21st century. Resection rates varied greatly across countries and appeared not optimal. Various factors associated with resection were revealed. Our findings identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based management strategies.

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An individual's inherited genetic variation may contribute to the 'angiogenic switch', which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.

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Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Efrina-B2/genética , Proteína Jagged-1/genética , Metaloproteinasa 2 de la Matriz/genética , Neovascularización Patológica/genética , Polimorfismo de Nucleótido Simple , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/diagnóstico , Neovascularización Patológica/mortalidad , Neovascularización Patológica/patología , Oportunidad Relativa , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Transducción de Señal

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INTRODUCTION: Fecal immunochemical tests (FITs) for hemoglobin are increasingly used in colorectal cancer (CRC) screening. The use of uniform positivity thresholds (cutoffs) within screening populations is expected to imply lower positive predictive values (PPVs) and higher numbers of colonoscopies needed (numbers needed to scope [NNSs]) to detect advanced neoplasms among screening participants at lower risk compared with those at higher risk. We aimed to assess such variation and its potential implications in a large screening cohort. METHODS: A quantitative FIT (FOB Gold; Sentinel Diagnostics, Milan, Italy) was conducted in fecal samples collected by 4,332 participants of screening colonoscopy before bowel preparation. Participants were classified into 3 risk groups (low, medium, and high) by tertiles of a previously derived risk-factor-based risk score. We determined the variation of PPVs and NNSs for detecting advanced neoplasms (i.e., CRC or advanced adenoma) when using the same FIT cutoffs and variation of FIT cutoffs that would yield uniform PPVs across risk groups. RESULTS: When a fixed FIT cutoff of 10 µg/g was used, the PPV increased from 23.3% to 41.8% from the low- to the high-risk group, with NNS decreasing from 4.3 to 2.4 (P < 0.001). Similar variations of PPVs and NNSs across risk groups were observed at higher FIT cutoffs. When risk group-specific cutoffs were defined to achieve fixed PPVs of 25%, 30%, and 35% across all risk groups, cutoffs varied from 5.3 to 11.4, 6.5 to 18.7, and 7.5 to 31.0 µg hemoglobin/g feces, respectively, between high- and low-risk groups (P < 0.05 for all differences). DISCUSSION: Using risk-adapted cutoffs may help to achieve target levels of PPV and NNS and might be an option to consider for personalized FIT-based CRC screening.

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Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/inmunología , Heces/química , Inmunoquímica/métodos , Anciano , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo

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OBJECTIVE: Fecal immunochemical tests (FITs) detect the majority of colorectal cancers (CRCs), but evidence for variation in sensitivity according to the CRC stage is sparse and has not yet been systematically synthesized. Thus, our objective was to systematically review and summarize evidence on the stage-specific sensitivity of FITs. METHODS: We screened PubMed, Web of Science, Embase, and the Cochrane Library from inception to June 14, 2019, for English-language articles reporting on the stage-specific sensitivity of FIT for CRC detection using colonoscopy as a reference standard. Studies reporting stage-specific sensitivities and the specificity of FIT for CRC detection were included. Summary estimates of sensitivity according to the CRC stage and study setting (screening cohorts, symptomatic/diagnostic cohorts, and case-control studies) were derived from bivariate meta-analysis. RESULTS: Forty-four studies (92,447 participants including 3,034 CRC cases) were included. Pooled stage-specific sensitivities were overall very similar but suffered from high levels of imprecision because of small case numbers when calculated separately for screening cohorts, symptomatic/diagnostic cohorts, and case-control studies. Pooled sensitivities (95% confidence intervals) for all studies combined were 73% (65%-79%) for stage-I-CRCs and 80% (74%-84%), 82% (77%-87%), and 79% (70%-86%) for the detection of CRC stages II, III, and IV, respectively. Even substantially larger variation was seen in sensitivity by T-stage, with summary estimates ranging from 40% (21%-64%) for T1 to 83% (68%-91%) for T3-CRC. DISCUSSION: Although FITs detect 4 of 5 CRCs at stages II-IV, the substantially lower sensitivity for stage-I-CRC and, in particular, T1 CRC indicates both need and potential for further improvement in performance for the early detection of CRC.

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Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Estadificación de Neoplasias/métodos , Colonoscopía , Neoplasias Colorrectales/metabolismo , Heces/química , Humanos , Inmunoquímica

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Early detection of colorectal neoplasms can reduce the disease burden of colorectal cancer by timely intervention of individuals at high risk. Our aim was to evaluate a joint environmental-genetic risk score as a risk stratification tool for early detection of advanced colorectal neoplasm (ACRN). Known environmental risk factors and high-risk genetic loci were summarized into risk scores for ACRN in 1014 eligible participants of a screening study. The performances of single and joint environmental-genetic scores were evaluated with estimates and 95% confidence intervals (CI) of the absolute risk, relative risk and predictive ability using the area under the curve (AUC). Individuals with higher environmental risk scores showed increasing ACRN risk, with 3.1-fold for intermediate risk and 4.8-fold for very high risk, compared to the very low environmental risk group. Similarly, individuals with higher genetic risk scores showed increasing ACRN risk, with 2.2-fold for intermediate risk and 3.5-fold for very high risk, compared to the lowest genetic risk group. Moreover, the joint environmental-genetic score improved the ACRN risk stratification and showed higher predictive values (AUC = 0.64; 95%CI = 0.60-0.67) with substantial difference (p = 0.0002) compared to the single environmental score (0.58; 0.55-0.62). The integration of environmental and genetic factors looks promising for improving targeting individuals at high-risk of colorectal neoplasm. Applications in practical screening programs require optimization with additional genetic and other biomarkers involved in colorectal carcinogenesis.

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Neoplasias Colorrectales/epidemiología , Detección Precoz del Cáncer/estadística & datos numéricos , Factores de Edad , Anciano , Colonoscopía/estadística & datos numéricos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/etiología , Femenino , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Alemania/epidemiología , Humanos , Estilo de Vida , Masculino , Anamnesis , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo/métodos , Factores de Riesgo

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OBJECTIVES: Many risk scores have been proposed to predict presence of advanced colorectal neoplasms, but a comprehensive comparison conducted in the same population is sparse. The aim of this study was to evaluate and directly compare the diagnostic performance of published risk prediction models for advanced colorectal neoplasms. METHODS: Data were drawn from 2 cohorts of subjects undergoing screening colonoscopy in Germany, i.e., KolosSal (n = 16,195) and BliTz (n = 7,444). Absolute risks and relative risks were generated for the presence of at least 1 advanced neoplasm, taking the lowest risk group as the reference group. Performance of risk models was assessed by the area under the receiver operating characteristic curve (AUC) and compared by the net reclassification improvement. RESULTS: The 2 cohorts included 1,917 (11.8%) and 848 (11.4%) participants with advanced neoplasm, respectively. Absolute risks were mostly between 5% and 10% among participants in the lowest risk group and between 15% and 20% among participants in the highest risk group, and relative risks mostly ranged from 2.0 to 4.0 across the risk models in both cohorts. The AUCs ranged from 0.58 to 0.65 in KolosSal and from 0.57 to 0.61 in BliTz for all risk scores. Compared to models with lower AUC, classification was significantly improved in most models with higher AUC. DISCUSSION: Risk models for advanced colorectal neoplasms generally yielded modest discriminatory power, despite some variation in performance between models. Future studies should evaluate the performance of these risk models in racially diverse populations and investigate possible extensions, such as combination with polygenic risk scores.

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Adenoma/epidemiología , Carcinoma/epidemiología , Neoplasias Colorrectales/epidemiología , Adenoma/diagnóstico , Adenoma/patología , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Antiinflamatorios no Esteroideos/uso terapéutico , Área Bajo la Curva , Aspirina/uso terapéutico , Índice de Masa Corporal , Carcinoma/diagnóstico , Carcinoma/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Dieta/estadística & datos numéricos , Detección Precoz del Cáncer , Ejercicio Físico , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Curva ROC , Grupos Raciales/estadística & datos numéricos , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Fumar/epidemiología , Circunferencia de la Cintura

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BACKGROUND: Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I-II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. METHODS: Data of stage I-II PaC patients resected and receiving chemotherapy in 2003-2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. RESULTS: A total of 11,837 resected PaC patients were analyzed, with median survival time of 18-23 months and 3-year survival rates of 21-31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. CONCLUSIONS: In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly.

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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/secundario , Adenocarcinoma/patología , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Pronóstico , Neoplasias Pancreáticas

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OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

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Neoplasias Pancreáticas/cirugía , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Sistema de Registros , Programa de VERF , Análisis de Supervivencia , Estados Unidos/epidemiología

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BACKGROUND: Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis. METHODS: Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression. RESULTS: Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable-adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50-4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (Ptrend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45-6.58, Ptrend = 0.005), 2.24 (95% CI, 1.18-4.44, Ptrend = 0.021) and 3.92 (95% CI, 1.51-12.18, Ptrend = 0.003), respectively. CONCLUSIONS: Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening.

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Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Factores de Crecimiento de Fibroblastos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Alemania , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Placebos , Estudios Prospectivos

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OBJECTIVES: Most studies identifying inflammatory markers for early detection of colorectal cancer (CRC) were conducted using clinically manifest cases. We aimed to identify circulating inflammatory biomarkers for early detection of CRC and validate them in both a clinical setting and a true screening setting. STUDY DESIGN AND SETTING: A total of 92 inflammatory proteins were quantified in baseline plasma samples from individuals clinically diagnosed with CRC and neoplasm-free controls matched on age and sex (training set). A multimarker panel was selected and evaluated in samples from another clinical setting (validation set C) and a screening setting (validation set S). RESULTS: In the training set (N = 330), a five-biomarker signature was selected that provided an area under curve (AUC) of 0.85 and 60.9% sensitivity to detect CRC at 90% specificity. When this algorithm was applied to validation set C (N = 318), the AUC (0.80) and sensitivity (49.5%) at 90% specificity for CRC diagnosis were only slightly lower than those in the training set. By contrast, the diagnostic performance of the algorithm in validation set S (N = 126) from a true screening setting was much poorer, with an AUC of 0.59 and a sensitivity of 28.6% at 90% specificity. CONCLUSIONS: An inflammation-related protein panel with apparently good diagnostic properties for CRC detection was identified and confirmed in an independent clinical validation set. However, the biomarker combination performed substantially worse in a validation sample from a true screening setting. Our results underline the importance of validation in screening settings subsequently to novel signature discovery for cancer early detection.

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Biomarcadores de Tumor/inmunología , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Área Bajo la Curva , Neoplasias Colorrectales/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad

RESUMEN

BACKGROUND: The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. METHODS: Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003-2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003-2005, 2006-2008, and 2009-2011) were further examined using the log-rank test. RESULTS: In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20-34% (< 60 years), 14-25% (60-69 years), and 9-13% (≥ 70 years) in stages I-II PaC; and 2-5% (< 60 years), 1-2% (60-69 years), and < 1-1% (≥ 70 years) in stages III-IV cancer. Patients who underwent operation had higher 3-year survival in each stage and age group (stages I-II: 23-39% (< 60 years), 16-31% (60-69 years), and 17-30% (≥ 70 years); stages III-IV: 5-19% (< 70 years) and 2-14% (≥ 70 years)). Perioperative survival also decreased with advancing stage and older age (stages I-II: 98-100% (< 60 years), 97-99% (60-69 years), and 94-99% (≥ 70 years); stages III-IV: 94-99% (< 70 years) and 81-96% (≥ 70 years)). Between 2003 and 2005 and 2009-2011, for overall PaC, both short-term and long-term survival improvements were observed in all countries except Belgium; for resected disease, short-term improvements were present only in the USA and Slovenia, but long-term improvements were observed in all countries except Slovenia, with stage-specific variations. CONCLUSIONS: Our large international study provides TNM stage- and age-specific population-based survival in overall and resected PaC that will facilitate clinical counseling. While the survival expectations for patients with resected PaC are substantially higher than the widely available and known dismal survival predictions for overall patients, conclusions on the benefits of resection cannot be made from this observational study. Patients with advanced-stage disease and/or older age should undergo careful risk assessment before treatment. Limited but inspiring improvement in survival is observed.

Asunto(s)

Pancreatectomía/estadística & datos numéricos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Europa (Continente)/epidemiología , Femenino , Historia del Siglo XXI , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pancreatectomía/historia , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Sistema de Registros , Programa de VERF , Estados Unidos/epidemiología

RESUMEN

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

Asunto(s)

Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Anciano , Quimioterapia Adyuvante , Terapia Combinada , Europa (Continente)/epidemiología , Medicina Basada en la Evidencia , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/cirugía , Vigilancia de la Población , Radioterapia Adyuvante , Programa de VERF , Factores de Tiempo , Estados Unidos/epidemiología

RESUMEN

Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5-FU-based chemotherapy and assessed pathway-specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow-up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet  = 0.81, 95% CI: 0.67-0.97; TYMS: rs1001761: HRhet  = 0.82, 95% CI: 0.68-0.99 and rs2847149: HRhet  = 0.82, 95% CI: 0.68-0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet  = 1.28, 95% CI: 1.07-1.53; HRhzv  = 2.02, 95% CI:1.46-2.80; HRlogAdd  = 1.31, pFDR  = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene-chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM-related genes could be associated with CRC survival and may modify effects of 5-FU-based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies.

RESUMEN

DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92

Asunto(s)

Neoplasias Colorrectales/genética , Metilación de ADN , Perfilación de la Expresión Génica/métodos , Análisis de Secuencia de ADN/métodos , Bases de Datos Genéticas , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Proteínas HMGA/genética , Humanos , Aprendizaje Automático , Regiones Promotoras Genéticas

RESUMEN

BACKGROUND & AIMS: The presence of specific single nucleotide polymorphisms (SNPs) can be used to calculate an individual's risk for colorectal cancer (CRC), called a genetic risk score (GRS). We investigated whether GRS can identify individuals with clinically relevant neoplasms in a screening colonoscopy population. METHODS: We derived a GRS based on 48 SNPs associated with CRC, identified in a comprehensive literature search. We obtained genetic data from 1043 participants (50-79 years old) in a screening colonoscopy study in Germany, recruited from 2005 through 2013 (294 with advanced neoplasms, 249 with non-advanced adenoma (NAAs), and 500 without neoplasms). Each participant was assigned a GRS by aggregating their risk alleles (0, 1, or 2). Risk of advanced neoplasms and NAA according to GRS was calculated by multiple logistic regression. Risk advancement periods were calculated. We replicated our findings using data from a subset of the Tennessee Colorectal Polyp Study. RESULTS: An increased GRS was associated with higher prevalence of advanced neoplasms, but not NAAs. Participants in the middle and upper tertiles of GRS had a 2.2-fold and 2.7-fold increase in risk, respectively, of advanced neoplasms compared to those in the lower tertile. Adjusted odds ratios (ORs) were 1.09 (95% confidence interval [CI], 0.76-1.57) for NAA in the middle tertile and 1.05 (95% CI, 0.70-1.55) for NAA in the upper tertile. The ORs were largest for proximal advanced neoplasms for participants in the middle tertile (OR, 3.55; 95% CI 1.85-6.82) and the upper tertile (OR, 3.61; 95% CI 1.84-7.10). The risk advancement period for medium vs low GRS was 13.4 years (95% CI 4.8-22.0) and for high vs low GRS was 17.5 years (95% CI, 7.8-27.3). CONCLUSIONS: In a genetic analysis of participants in a CRC screening study in Germany, an increased GRS (based on CRC-associated SNPs) was associated with increased prevalence of advanced neoplasms. These findings might be used in defining risk-adapted screening ages.

Asunto(s)

Adenoma/genética , Carcinoma/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Adenoma/diagnóstico , Adenoma/epidemiología , Adenoma/patología , Anciano , Carcinoma/diagnóstico , Carcinoma/epidemiología , Carcinoma/patología , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer , Femenino , Alemania/epidemiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Prevalencia , Medición de Riesgo , Tennessee/epidemiología